Method and apparatus for determining familial risk of disease

ABSTRACT

Personal and family health history information can be used to assess familial risk of disease. For example, information can be collected about the disease history of a person and the person&#39;s first- and second-degree relatives and then analyzed to determine the familial risk of common diseases such as coronary heart disease, stroke, type 2 diabetes, and colorectal, breast, and ovarian cancer. Assessed familial risk of disease can then be used by researchers to better estimate the contribution of personal history and family history to the etiology and natural history of a disease of interest, and by consumers and health professionals to determine recommendations for disease management, prevention and screening that are personalized and targeted to the familial risk. Other embodiments are also described and claimed.

This patent application claims the benefit of the earlier filing date ofU.S. provisional application Ser. No. 60/650,076 entitled “Familial RiskAnalysis for Determining a Disease Prevention Plan”, filed Feb. 3, 2005.

FIELD

The field relates to preventative medicine and risk analysis of disease.

BACKGROUND

Determining risk factors for a disease can be helpful in managing adisease, and for assessing an individual's overall risk for a diseaseand in creating a plan to modify an individual's risk of developing adisease. Medical providers are under increasing pressure fromgovernments, medical specialty organizations, managed care, and patientsto practice preventative medicine. Similarly, health organizations andinsurance companies are beginning to recognize that risk analysis ofdisease and preventative medicine can be a cost effective strategy forproviding care. Medical screening and prevention guidelines for manychronic disorders have been developed by governmental and medicalorganizations to facilitate risk analysis of disease and preventivemedicine practice. However, such guidelines can be slow to be adopted,sometimes poorly understood, counter to historical practice, and can beperceived as cumbersome, difficult to use, not readily accessible, orconfusing by both medical providers and patients. Similarly, theguidelines do not incorporate comprehensive personalized family healthhistory information to determine a patient-specific or personalized riskof disease and disease prevention plan. Accordingly, there remains aneed to better assess disease risk and communicate risk to patients. Inaddition, clinical trials and epidemiologic investigations of riskfactors for disease often fail to adequately assess the family historyas a risk factor, often using limited definitions of family history.Improved assessment of familial risk in these investigations could helpin elucidating the role of family history as a disease risk factor, andthe potential role of genes in the development or natural history ofdisease.

SUMMARY

Personal and family health history information can be used to assess thefamilial risk of diseases and to determine disease management optionsand early detection and prevention strategies. For example, informationcan be collected about the disease history of a person and the person'sfirst- and second-degree relatives (e.g., mother, father, children,siblings, grandparents, aunts and uncles) and then analyzed to determinethe familial risk for one or more diseases (e.g., coronary heartdisease, stroke, type 2 diabetes, and colorectal, breast, and ovariancancer). Assessed familial risk of disease can then be used to stratifya clinical or research population into different levels of familialrisk, and to determine recommendations for disease management,prevention and screening that are specific to the familial risk level.

The techniques described herein can be applied to any number of diseasesin medical and non-medical settings where determining the familial riskof disease is desired.

Additional features and advantages of the technologies described hereinwill be made apparent from the following detailed description ofillustrated embodiments, which proceeds with reference to theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The embodiments of the invention are illustrated by way of example andnot by way of limitation in the figures of the accompanying drawings inwhich like references indicate similar elements. It should be noted thatreferences to “an” embodiment of the invention in this disclosure arenot necessarily to the same embodiment, and they mean at least one.

FIG. 1 is a flowchart showing an example method for determining familialrisk of disease for a subject.

FIG. 2 is a flowchart showing an example method for determining familialrisk of one or more diseases of interest for a subject.

FIG. 3 is a flowchart showing an example method for determining asubject's familial risk of a disease of interest based on first- andsecond-degree relative family health history.

FIG. 4 is a flowchart showing an example computer-implemented method fordetermining familial risk of one or more diseases of interest.

FIG. 5 is a flowchart showing yet another example method for determiningfamilial risk of disease for a subject.

FIG. 6 illustrates an example familial risk matrix for determiningfamilial risk of disease based on personal and family health histories.

FIGS. 7-24 are example familial risk matrices for determining familialrisk of breast cancer.

FIG. 25 is a block diagram of a computer system that can implementfamilial risk matrices and their uses.

DETAILED DESCRIPTION

Overview of Technologies

The technologies described herein can be used in a variety of scenariosin which determination of the familial risk of one or more diseases ofinterest is useful.

A disease of interest includes any disease for which familial risk isassessed for a subject. In practice, diseases of interest include commondiseases that result from complex interactions of multiple genes withmultiple environmental factors. For example, coronary heart disease,stroke, diabetes, colorectal cancer, breast cancer, and ovarian cancercan be diseases of interest.

An indicator disease includes any disease associated with indicating orotherwise correlating with the risk of developing a disease of interest.For example, ovarian cancer can be an indicator disease for breastcancer, and coronary heart disease can be an indicator disease forstroke.

An indicator trait includes any trait associated with indicating orotherwise correlating with the risk of developing a disease of interest.For example, smoking can be an indicator trait for lung cancer, smokingcan be an indicator trait for heart disease, a mutation in the MSH2 geneor MLH1 gene can be an indicator trait for colorectal and endometrialcancer, and Ashkenazi Jewish ancestry can be an indicator trait forbreast and ovarian cancer.

A first-degree relative includes blood relatives, such as parents,siblings, or children. First-degree relatives share one half of theirgenes in common.

A second-degree relative includes aunts, uncles, nieces, nephews,half-siblings, and grandparents. Second-degree relatives share onequarter of their genes in common.

Family health history information includes disease history of asubject's biological relatives. For example, family health historyinformation can include disease history of first- and second-degreerelatives, as well as disease history of more distant relatives. Diseasehistory, for example, can include the number of first- and second-degreerelatives, if a relative has or has had a disease of interest, indicatordisease or indicator trait, sex of affected relatives, lineage ofaffected relatives (e.g., nuclear, maternal or paternal side of thefamily), type of affected relative (e.g., sibling or parent), and theage of the relative at time of diagnosis of a disease of interest,indicator disease or indicator trait.

Personal health history information includes demographic informationsuch as age, date of birth, sex, and race/ethnicity; anthropometric andphysiologic traits such as height, weight, waist circumference, bloodcholesterol and blood pressure; medical history such as whether thesubject currently has or previously has had a disease or a disease riskfactor (e.g., a disease of interest or an indicator disease or trait);personal health behavior information, and the like; or any combinationthereof.

Personal health behavior information includes information related tosmoking, exercise, diet, screening tests, and the like.

Screening tests include any test that screens for disease or riskfactors associated with disease. For example, screening tests caninclude clinical breast exams, mammograms, fecal occult blood tests,sigmoidoscopy, colonoscopy, blood cholesterol test, blood pressure test,blood sugar test, and the like.

Familial risk of disease includes a likelihood of developing a diseasebased on personal and family health histories. In other words, thefamilial risk of disease describes the strength of the personal andfamily health histories as a risk factor for a disease of interest. Forexample, familial risk of a disease of interest can be categorized ashigh (e.g., strong), moderate, or low (e.g., weak) based on the numberof first- and second-degree relatives having the disease of interest, anindicator disease or indicator trait, and the relatives' age of onset ofthe disease of interest or indicator disease, and the like. For mostcommon diseases, compared to weak familial risk, having a moderatefamilial risk may be associated with about a 2-fold increase, and havinga strong familial risk may be associated with about a 3-fold or greaterincrease in risk.

A predetermined personal disease history scenario includes any personalhealth history information that may be associated with increased ordecreased risk for a disease of interest. For example, having a personalhistory of a disease of interest at an early age of onset and having anindicator trait can be a predetermined personal disease historyscenario, and having a personal history of an indicator diseaseassociated with a disease of interest at a late age of onset can be apredetermined personal disease history scenario.

A predetermined familial disease history scenario includes any familyhealth history information that may be associated with increased ordecreased risk for a disease of interest. For example, having afirst-degree relative with a disease of interest at a late age of onsetcan be a predetermined familial disease history scenario, and having twosecond-degree relatives from the same lineage with an indicator diseaseat an early age of onset is another example of a predetermined familialdisease history scenario.

Intersection of predetermined personal and familial disease historyscenarios includes situations in which the predetermined personal andfamilial disease history scenarios are referenced with one ore morefamilial risk matrices for the disease of interest. According to anembodiment of the invention, for any given predetermined personaldisease history scenario, a minimum of two predetermined familialdisease history scenarios that describe family history information willmeet in a familial risk-indicating cell within the matrix. The level offamilial risk (e.g., weak, moderate or strong) is assigned based on theintersection of the three scenarios As an example, a three dimensionalmatrix may be defined whose “axes” are 1) personal disease historyscenarios, 2) first familial disease history scenarios, and 3) secondfamilial disease history scenarios. Note that for any givenpredetermined personal disease history scenario the assigned familialrisk of disease of interest could be based on several intersectionsobtained from several different predetermined familial disease historyscenarios identified within a matrix for a disease of interest. In thatcase, the cell with the highest magnitude of risk is selected in orderto assign the familial risk of disease.

Familial risk clarifiers include qualifying statements, which clarify orfurther explain the assignment of familial risk of a disease of interestby describing the elements of the personal or family history that areassociated with the level of familial risk, and the possibility that thepersonal and family histories are suggestive of an inherited syndrome.For example, familial risk clarifiers can be used in the explanation offamilial risk to subjects and health professionals, can inform genetictesting decisions, and can be used to tailor a disease prevention plan.

EXAMPLES

In any of the examples herein, an age of onset of disease or age atfirst diagnosis of a disease or trait can be an age range, particularage, age category (e.g., early, late, or the like), or other indicationof age. Although particular ages are shown in some examples (e.g.,early-onset, late-onset), other ages can be used.

Example 1 Example Method for Determining Familial Risk of Disease ofInterest for a Subject

FIG. 1 shows an example method 200 for determining familial risk ofdisease for a subject.

At 202, personal and family health histories are collected. For example,disease history of a subject and a subject's first- and second-degreebiological relatives can be collected, including the sex of the subject,and the number, sex, type and lineage of the subject's first- andsecond-degree relatives, and whether the subject or a relative has orhas had the disease of interest, or an indicator disease or indicatortrait associated with that disease of interest, and the age of thesubject and relative at the time of first diagnosis or onset of thedisease of interest, indicator disease or indicator trait.

At 204, familial risk of the disease of interest is determined byanalyzing personal and family health histories. For example,predetermined personal and familial disease history scenarios can beanalyzed.

At 206, results of the determination of the familial risk of a singledisease of interest are presented. For example, the familial risk of adisease of interest can be presented as high (e.g., strong), moderate,or low (e.g., weak). Familial risk clarifiers can also be presented.

The method described in this or any of the other examples can be acomputer-implemented method performed via computer-executableinstructions in one or more computer-readable media. Any of the actionsshown can be performed by software incorporated within an electronicmedical record system or any other health information system, or adatabase supporting clinical trials or epidemiologic research.

Example 2 Example Method for Determining Familial Risk of One or MoreDiseases of Interest for a Subject

FIG. 2 shows an example method 300 for determining the familial risk ofone or more diseases of interest for a subject.

At 302, personal and family health histories of a subject are received.For example, disease history of a subject and a subject's first- andsecond-degree biological relatives can be received, including thenumber, lineage, type and sex of first- and second-degree relatives, andwhether the subject or a relative has or has had diseases of interest,or an indicator disease or an indicator trait associated with thosediseases of interest, and the age of the subject and relatives at thetime of first diagnosis or onset of the diseases of interest, indicatordiseases or indicator traits.

At 304, a disease of interest is determined. For example, heart disease,stroke, diabetes, colorectal cancer, breast cancer, and ovarian cancercan be diseases of interest that are determined.

At 306, the familial risk of the determined disease of interest can beassigned for a subject. For example, the personal health history of asubject and the family health history of a subject's first- andsecond-degree biological relatives can be analyzed to assign the levelof familial risk for the disease of interest. Following the assignmentof the familial risk for the determined disease of interest, one or moreadditional diseases of interest can be determined at 304, and the levelof familial risk for the one or more additional diseases of interest canbe assigned.

At 308, results of the assignment of the familial risk for the one ormore diseases of interest can be presented. For example, the familialrisk can be categorized as low (e.g., weak), moderate, or high (e.g.,strong) and presented to the subject with accompanying familial riskclarifiers.

Example 3 Example Method for Determining a Subject's Familial Risk of aDisease of Interest Based on Personal Health History and First- andSecond-Degree Relative Family Health History

FIG. 3 shows an example method 400 for determining a subject's familialrisk of a disease of interest based on personal health history andfirst- and second-degree relative family health history.

At 402, personal and family health histories for a subject are obtained.Personal and family health histories can be obtained in real-time fromthe subject or another historian (e.g., a family member) or via thesubject's paper or electronic health records, or from paper orelectronic forms used for clinical or epidemiological research. Forexample, personal and family health histories for a subject can beobtained via completed questionnaires in an electronic or paper format.

At 404, a disease of interest is determined, for example by the consumerherself or by a health professional or researcher. For example, heartdisease, stroke, diabetes, colorectal cancer, breast cancer, and ovariancancer can be diseases of interest that are determined.

At 406, whether a subject has or has had the disease of interest isdetermined from the personal health history, and the number of first-and second-degree relatives that have or have had the disease ofinterest is determined from the family health history.

At 408, if the subject has or has had the disease of interest, then theage of onset of the disease of interest is determined from the personalhealth history, and if first- and second-degree relatives have or havehad the disease of interest, then the age of onset of the disease ofinterest is determined from the family health history. Lineage and sexof the first- and second-degree relatives that developed the disease ofinterest are also determined.

At 410, whether a subject has or has had a different disease associatedwith the disease of interest (e.g., an indicator disease) is determinedfrom the personal health history, and the number of first- andsecond-degree relatives that have or have had an indicator disease isdetermined from the family health history.

At 412, if the subject has or has had an indicator disease, then the ageof onset of the indicator disease is determined from the personal healthhistory, and if first- and second-degree relatives have or have had theindicator disease, then the age of onset of the indicator disease isdetermined from the family health history. Lineage and sex of the first-and second-degree relatives that have or have had the indicator diseaseare also determined.

At 414, a subject's familial risk of the disease of interest based onthe personal health history and first- and second-degree relative familyhealth history is assigned. For example, the familial risk can beassigned as low (e.g., weak), moderate, or high (e.g., strong) based onthe personal and family health histories (e.g., by detection of theintersection of predetermined personal and familial disease historyscenarios).

At 416, results of the assignment of familial risk for one or morediseases of interest can be presented. For example, familial risk can becategorized as low (e.g., weak), moderate, or high (e.g., strong) andpresented to the subject with accompanying familial risk clarifiers.

Example 4 Example Computer-Implemented Method for Determining FamilialRisk of One or More Diseases of Interest

FIG. 4 shows an example computer-implemented method 500 for determiningthe familial risk of one or more diseases of interest.

At 502, personal health history and family health history is received.For example, disease history of a subject and a subject's first- andsecond-degree biological relatives can be received, including thenumber, sex, type, and lineage of first- and second-degree relatives,and whether the subject or a relative has or has had a disease ofinterest or an indicator disease or indicator trait associated with thedisease of interest, and the age of the relative at the time of firstdiagnosis or onset of the disease of interest or indicator disease ortrait.

At 504, the familial risk of one or more diseases of interest isdetermined based on personal health history and first- and second-degreefamily health history of one or more diseases of interest or indicatordiseases or indicator traits.

At 506, results of the assignment of the familial risk for the one ormore diseases of interest can be presented. For example, the familialrisk can be categorized as low (e.g., weak), moderate, or high (e.g.,strong) and presented with accompanying familial risk clarifiers.

Example 5 Another Example Method for Determining Familial Risk of aDisease of Interest for a Subject

FIG. 5 shows another method 700 for determining the familial risk of adisease of interest for a subject.

At 702, health records are received. For example, personal healthhistory records and health records of one or more relatives can bereceived. The health records can include the disease history of asubject and a subject's first- and second-degree biological relatives,including the number, sex, type, and lineage of first- and second-degreerelatives, and whether the subject or a relative has or has had adisease of interest, or an indicator disease or indicator traitassociated with that disease of interest, and the age of the subject orrelative at the time of first diagnosis or onset of the disease ofinterest, indicator disease or indicator trait. Additionally, healthrecords can include personal health history information such as age,date of birth, sex, race/ethnicity, height, weight, and personal healthbehavior information, or any combination thereof.

At 704, familial disease data can be determined from the health recordsreceived. For example, disease history of a subject and a subject'sfirst- and second-degree biological relatives can be determined,including the number, sex, type, and lineage of first-and second-degreerelatives, and whether the subject or a relative has a disease ofinterest or an indicator disease or indicator trait associated with thatdisease of interest, and the age of the subject or relative at the timeof first diagnosis or onset of the disease of interest, indicatordisease or indicator trait.

At 706, familial risk matrices for one or more diseases of interest canbe consulted to determine the familial risk of one or more diseases forthe subject based on the determined familial disease data. For example,predetermined personal and familial disease history scenarios (e.g.,disease data on the subject and first- and second-degree relatives) canbe compared to the familial risk matrices (e.g., matrices that assign alevel of familial risk for a disease of interest) by identifying theintersections of predetermined personal and familial disease historyscenarios.

At 708, results of the consultation of the familial risk matrices forone or more diseases of interest can be provided as results of thedetermination of the familial risk of disease. For example, anintersection of one predetermined personal disease history scenario andtwo predetermined familial disease history scenarios can result in anassignment of a level of familial risk. Additionally, familial riskclarifiers can be provided with the results to clarify or furtherexplain the determination of the familial risk of disease.

Example 6 Example Familial Risk Matrix for Determining the Familial Riskof a Disease of Interest Based on Personal and Family Health History

FIG. 6 illustrates an example familial risk matrix 800 for determiningthe familial risk of a disease of interest based on personal healthhistory and family health history. The matrix may also be referred to asan array. Such a matrix can be used as a look-up table to assess asubject's familial risk of a disease of interest in any of the examplesherein.

In this example, the familial risk matrix 800 is a conceptual,three-dimensional (“3D”) matrix or array: One “axis” of the 3D matrixincludes predetermined personal disease history scenarios 801 (e.g., a,b, c, . . . ), another axis of the matrix includes predeterminedfamilial disease history scenarios 802 (e.g., A, B, C, . . . ) and thethird axis of the matrix includes predetermined familial disease historyscenarios 804 (e.g., 1, 2, 3 . . . ). The matrices 803_1, 803_2, . . .represented by the combination of different scenarios may be ofdifferent sizes and may have different qualities, that is they need notall refer to the same set of personal and/or familial disease historyscenarios.

The predetermined familial disease history scenarios 804 and 802 can bebased on the number of first- and/or second-degree relatives from onelineage (e.g., nuclear, maternal or paternal) having a disease ofinterest, an indicator disease or indicator trait, the age of therelative at the time of first diagnosis or onset of the disease ofinterest, the indicator disease or indicator trait, and the type and sexof the relative. In matrices in which breast cancer or ovarian cancer isthe disease of interest, for example, Ashkenazi Jewish ancestry is anindicator trait that can also be included in a predetermined personal orfamilial disease history scenario, i.e. in any one or more of scenarios801, 802, and 804.

The intersection of two predetermined familial disease history scenarios802, 804 in the context of a predetermined personal disease historyscenario 801, such as (a, B, 2), results in a cell 806, which includes arisk assessment category (e.g., “Risk”) being assigned based on theintersection of the three scenarios. In the preferred embodiment of theinvention, one of only three levels of familial risk for a disease ofinterest can be assigned (represented by uppercase letters): low or weakfamilial risk (A), moderate familial risk (M), or strong or highfamilial risk (H). If more than one intersection is found within amatrix, then the intersection with the highest level of risk willdetermine the assigned level of familial risk. Furthermore, familialrisk clarifiers (e.g., “Clarifiers”) can be included with the assignmentof risk, thereby incorporating references to qualifying statements whichclarify or further explain the assignment of familial risk of diseasebased on the intersection of at least one predetermined personal diseasehistory scenario and two predetermined familial disease historyscenarios. Such familial risk clarifiers can be represented by lowercase letters in the matrix and the references incorporated into theproviding and presentation of results. Such familial risk clarifiers canbe provided according to a hierarchy that considers the relevant familyhistory characteristics or patterns of disease in the family withoutredundancy or inconsistencies, as described in detail below.

Analysis of multiple intersections of two predetermined familial diseasehistory scenarios in the context of a personal disease history scenariocan result in an overall familial risk level determination for thedisease of interest. In the preferred embodiment of the invention, thehighest familial risk level determined can be selected as the overallfamilial risk level determination for the disease of interest.

The creation of familial risk matrices for a disease of interest, suchas breast cancer, are described in detail below. The method of familialrisk stratification using the matrices described herein can be utilizedfor any disease of interest if personal and/or family health historiesare risk factors for the disease of interest.

In constructing such matrices, the basic structure may remain constant,representing the elements of a family tree (pedigree), for exampleincluding the index case, first-degree relatives and second-degreerelatives. (More distant relatives can be included if such informationadds value to the risk assessment, although for most diseases this isnot the case). What may vary in the structure of the matrices, for anygiven disease of interest, are the types and numbers of indicatordiseases or indicator traits represented, as well as the relevance ofage of onset of a disease of interest or indicator disease or indicatortrait (e.g., may not be relevant at all, specific ages might berelevant, or several age groupings may be represented), and the sex ofrelatives or the type of relative (e.g., mother versus father) with adisease of interest or indicator disease or indicator trait may berepresented.

Rules regarding identification of the lineage of relatives may beconsistently followed for matrices of any given disease of interest, asthis allows for recognition of patterns of disease transmission(including diseases of interest and indicator diseases), such asautosomal dominant, autosomal recessive and X-linked modes oftransmission, that are suggestive of known hereditary syndromes that canfeature the disease of interest.

For any given disease of interest, the presence or absence of thatdisease of interest, and indicator diseases and indicator traitsassociated with that disease of interest, in a subject or a subject'srelatives, are represented by the intersections of personal and familialdisease history scenarios within a matrix. For any given disease ofinterest, a standard set of rules is followed to determine the strengthof the assigned familial risk level (e.g., weak, moderate, or strong)represented by each of the possible intersections or cells within amatrix. The basis for these rules of familial risk assignment is derivedfrom empirical data describing personal and family historycharacteristics that are specific to the disease of interest, or whensuch data are not available, general principles of familial riskassessment are followed. As new knowledge regarding personal and familyhistory characteristics associated with a disease of interest becomesavailable, the level of familial risk assigned and/or the clarifyingstatements explaining the familial risk assignment might change.

The structure of the familial risk matrices and the rules used todetermine familial risk stratification for a disease of interest allowfor flexibility to make changes in the matrices with relative ease toaccommodate new knowledge regarding those aspects of the familial riskstratification method which can vary, such as inclusion of more distantrelatives, change in the numbers and types of indicator diseases orindicator traits, change in the age of onset criteria, representation ofthe sex of relatives or the types of relatives within the matrices, orchange in the level of familial risk and the clarifying statementsrepresented within any given cell within the matrix that represents anintersection of two predetermined familial risk scenarios within thecontext of a predetermined personal disease history scenario.

Example 7 Example Familial Risk Matrices for Determining Familial Riskof Breast Cancer Based on Personal and Family Health Histories

FIGS. 7-24 illustrate example familial risk matrices (according to theform of example familial risk matrix (800) for determining familial riskof breast cancer based on personal health history and family healthhistory. Shaded areas of the matrices are duplicative cells that containredundant information found within each matrix. Note that by recognitionof disease associations and patterns in personal health history andfamily history that relate to other diseases, an approach similar to theabove can be taken to generate familial risk matrices for otherdiseases, e.g., coronary heart disease, stroke, colorectal cancer etc.

In the example, the definition of age of onset of breast cancer isdefined as:

Breast cancer: early, <age 50; late, > or =age 50 or age of onsetunknown

In the example, the definition of lineage is:

-   -   Nuclear: any combination of index case, siblings, or children    -   Maternal: any combination of mother, mother's siblings, or at        least one of mother's parents. Can include index case, index        case's siblings and index case's children    -   Paternal: any combination of father, father's siblings, or at        least one of father's parents. Can include index case, index        case's siblings and index case's children.

The familial risk stratification matrices for breast cancer recognizefamily history characteristics that are associated with an increasedrisk of breast cancer, as well as patterns of disease suggestive ofhereditary syndromes that feature breast cancer. The family historycharacteristics associated with increased risk of breast cancer arederived from the literature. There are at least six hereditary syndromesthat feature breast cancer. The two most common forms of hereditarysyndromes that feature breast cancer are hereditary breast-ovariancancer (HBOC) and hereditary site-specific breast cancer. Both areassociated with germline BRCA1 and BRCA2 mutations. Most families withHBOC have BRCA mutations, and about half of families with hereditarysite-specific breast cancer have BRCA mutations. The breast cancerfamilial risk matrices in FIGS. 7-24 recognize familial characteristicsthat are associated with an increased risk of breast cancer, as well asthe two common familial syndromes that feature breast cancer. With theaddition of other indicator diseases in the matrices, additional familyhistory associated with breast cancer could be identified, and otherrare hereditary syndromes that feature breast cancer could berecognized. For example, familial aggregation of breast, endometrial andthyroid cancer is suggestive of Cowden syndrome due to mutations in thePTEN gene. Familial aggregation of breast, brain, adrenalcortical cancerand sarcoma is suggestive of Li-Fraumeni syndrome due to mutations inthe TP53 gene.

The breast cancer familial risk matrix in FIGS. 7-24 is arranged as six(6) sets of three, two-dimensional tables or matrices. These correspondto eighteen (18) tables depicted in FIGS. 7-24, respectively.

The first set of tables consists of FIGS. 7-9. These are applicable to afemale user who has or has had both early onset breast cancer andovarian cancer (as the personal disease history scenario). The Y-axis(familial disease history scenarios) is the same for FIGS. 7 and 8,focusing on 1^(st) degree relatives of the user, whereas the Y-axis ofFIG. 9 focuses on her 2^(nd) degree relatives. The X-axis in FIG. 7focuses on 1^(st) degree relatives, whereas the X-axis in both FIGS. 8and 9 deals only with 2^(nd) degree relatives. Note that the assessedfamilial risk in all possible intersections of the first set is H(high), but there are differences in the risk clarifiers contained inthe intersections. An element of a matrix may include, in addition tothe risk level assignment, a reference to one or more risk clarifiersthat explain the risk level assigned by that element.

Familial risk clarifiers for the breast cancer matrices in FIGS. 7-24include:

-   -   a=At least one family member with both breast and ovarian        cancer. The combination of these cancers is a risk factor for        breast cancer and can be a sign of an inherited form of breast        cancer called hereditary breast-ovarian cancer.    -   b=Closely related family members with breast and ovarian cancer.        The combination of these two cancers is a risk factor for breast        cancer and can be a sign of an inherited form of breast cancer        called hereditary breast-ovarian cancer.    -   c=Two or more closely related family members with ovarian        cancer. Although a different cancer, a family history of ovarian        cancer is a risk factor for breast cancer and can be a sign of        an inherited form of breast cancer called hereditary        breast-ovarian cancer.    -   d=At least one family member with male breast cancer, which can        be a sign of an inherited form of breast cancer.    -   e=At least one family member with breast cancer at a young age.    -   f=Two or more closely related family members with breast cancer.    -   g=A family member with breast cancer at a later age.    -   h=A family member with ovarian cancer, which can be a risk        factor for breast cancer.    -   i=Three or more closely related family members with breast        cancer.    -   j=Some inherited forms of breast and ovarian cancer are more        common in Ashkenazi Jewish families.    -   k=Your personal history suggests the possibility of an inherited        form of cancer, which might increase your risk for developing        another cancer.    -   In all of the tables of FIGS. 7-24, if the assigned familial        risk at an intersection is H and the user is Ashkenazi Jewish,        then each element may also contain the j clarifier.

Turning now to FIGS. 10-12, these three tables are used to look up anassigned familial risk level when a female user has or has had bothlate-onset breast cancer and ovarian cancer. For such a user, the tablesin FIGS. 7-9 are not applicable. The X and Y axis scenarios of FIGS.10-12 are however the same as in FIGS. 7-9, respectively. Once again,the assessed familial risk in all intersections is H, but there aredifferences in the risk clarifiers, depending on the user's personal andfamily disease history.

Turning now to FIGS. 13-15, these three tables are used to look up anassigned familial risk level when a female user has or has hadearly-onset breast cancer and has no history of ovarian cancer, or whena male user has or has had breast cancer at any age of onset. The X andY axis scenarios are the same as in FIGS. 7-9, respectively. For such auser, the tables in FIGS. 7-12 are not applicable. Once again, theassessed familial risk in all intersections is H, but there aredifferences in the risk clarifiers, depending on the user's personal andfamily disease history.

The three tables in FIGS. 16-18 are used to look up an assigned familialrisk level when a female user has or has had late-onset breast cancerand no history of ovarian cancer. The X and Y axis scenarios are thesame as in FIGS. 7-9, respectively. For such a user, the tables in FIGS.7-15 are not applicable. The assessed familial risk is generally Hexcept for a small number of cases where there are no first- orsecond-degree relatives with breast and ovarian cancer (see for exampleelement 4-045 in FIG. 16). Note the differences in the risk clarifiersbetween elements 4-153 and 4-154 in FIG. 18, depending on the user'spersonal and family disease history.

The tables in FIGS. 19-21 are used when a female user has or has hadovarian cancer and no history of breast cancer.

The tables in FIGS. 22-24 are used when a user has no personal historyof breast or ovarian cancer.

Example 8 Example Hierarchy of Presentation of Familial Risk Clarifiersin Familial Risk Matrices for Determining Familial Risk of Breast CancerBased on Personal and Family Health History

Familial risk clarifiers in familial risk matrices for determiningfamilial risk of breast cancer (for instance, according to Example 7based on personal health history and family health history) can beprovided according to a hierarchy to ensure appropriate presentation ofexplanations of the level of familial risk without redundancy orinconsistencies. For example, a hierarchy utilizing familial riskclarifiers described in Example 7 can be as follows:

-   -   Familial risk clarifier “a” can be presented;    -   Familial risk clarifier “b” can be presented;    -   Familial risk clarifier “c” can be presented;    -   Familial risk clarifier “d” can be presented;    -   Familial risk clarifier “e” can be presented;    -   Familial risk clarifier “f” can be presented when familial risk        clarifier “i” is not presented;    -   Familial risk clarifier “g” can be presented if:        -   Familial risk clarifier “a” is not presented; or Familial            risk clarifier “b” is not presented; or Familial risk            clarifier “d” is not presented; or Familial risk clarifier            “e” is not presented; or Familial risk clarifier “f” is not            presented; or Familial risk clarifier “i” is not presented;    -   Familial risk clarifier “h” can be presented if:        -   Familial risk clarifier “a” is not presented; or Familial            risk clarifier “b” is not presented; or Familial risk            clarifier “c” is not presented;    -   Familial risk clarifier “i” can be presented;    -   Familial risk clarifier “j” can be presented; and    -   Familial risk clarifier “k” can be presented.

Example 9 Example Advantages and Applications of Technologies

While family history is a risk factor for most chronic diseases ofpublic health significance, it is underutilized in clinical andepidemiological investigations of diseases, and in the practice ofpreventative medicine and public health for assessing disease risk andinfluencing early detection and prevention strategies. Geneticists havelong recognized the value of family history for discovering inheriteddisorders, which are usually the result of single gene mutations.Although single gene disorders are typically associated with a largemagnitude of risk, they account for only a small proportion ofindividuals with a genetic risk for common, chronic diseases. Most ofthe genetic susceptibility to these disorders for most people is theresult of multiple genes interacting with multiple environmental factors(broadly defined as diet, exposures, behaviors, etc.). Family historytherefore, is more than genetics; it reflects the consequences ofinherited genetic susceptibilities and shared environment. All of thesefactors are important when estimating disease risk.

It is well known that people with close relatives with certain diseasessuch as heart disease, diabetes, and cancers, are more likely to developthose diseases themselves. Studies suggest that having a first-degreerelative with a chronic disease can at least double a person's risk ofdeveloping the same or a related disease compared to someone withoutthis history. This risk generally increases with an increasing number ofaffected relatives, especially if their disease was diagnosed at anearly age. Physicians usually collect information about a patient'sfamily history, but often do not discuss, revisit or update it overtime. As a result, they may miss opportunities to offer specificmanagement and prevention recommendations for diseases that run in thefamily. An embodiment of the invention uses personal and family healthhistories as a “genomics tool” that can capture the interactions ofgenetic susceptibilities and environmental risk factors shared by familymembers. Determining the familial risk for a disease (i.e., defining thestrength of an individual's personal and family health history as adisease risk factor) can aid in making personalized recommendations fordisease management and prevention, which should result in improvedhealth outcomes.

Healthcare information and resources are widely available to medicalproviders and patients via electronic and printed resources.Unfortunately, many informational sources provide only broad,generalized information. An embodiment of the invention provides userswith feedback regarding individualized risk assessment that isapplicable to their own personalized health care, while also beingsimple and easy to use and interpret. Systems and methods for collectinginformation about an individual's personal and family health historiesthat determine the strength of this information as a risk factor for adisease, and clarify the aspects of the history that are associated withthe disease or are suggestive of hereditary syndromes that can featurethe disease, can influence the clinical management and prevention ofdisease, and can provide risk stratification in clinical trials andepidemiologic investigations. Prevention strategies can includetargeting lifestyle changes such as diet, exercise, and smokingcessation; screening at earlier ages, more frequently, and with moreintensive methods than might be used for average-risk individuals; useof chemoprevention such as aspirin for heart disease or Tamoxifen forbreast cancer; and referral to a specialist for assessment of geneticrisk factors, including genetic testing.

Currently there is no standardized way to collect or interpret familyhealth history data for clinical practice or for use in clinical orepidemiologic research. Most healthcare professionals and researcherscollect family history information using paper-based tools that askquestions such as, “Do you have any first-degree relative with breastcancer?” and the clinicians and researchers often limit theirinterpretation of the collected data to “family history positive” or“family history negative” for the disease of interest withoutstratifying the familial risk. In addition, the interpretation may notconsider the presence of indicator diseases or traits that couldinfluence the risk of disease, or recognition of patterns of diseasethat may be suggestive of inherited syndromes.

Risk assessment tools that are used in clinical practice and researchmay also collect limited family history data resulting in limitedinterpretation of family history. For example, the Gail model projects awoman's individualized estimate of risk for invasive breast cancer overa 5-year period and over her lifetime (to age 90). The Gail modelinquires about several risk factors such as current age, race/ethnicity,age at menarche, age at first live birth, whether there is a history ofbreast biopsy and if so how many and were there signs of atypia orhyperplasia on the biopsy, and family history. However, the familyhistory is limited to asking how many first-degree relatives (i.e.,mother or sisters) have had breast cancer. It does not ask about malebreast cancer, or breast or ovarian cancer in children or second-degreerelatives, which are important questions for determining the level offamilial risk of breast cancer and the possibility of a hereditarysyndrome that can feature breast cancer. In contrast, the CancerGenegenetic risk assessment tool for cancer collects family history dataabout first- and second-degree relatives such as their age, sex, and ageat diagnosis of cancer, and this tool provides information regarding anabsolute lifetime risk for cancer and it estimates the likelihood thatan individual carries a mutation in one of the cancer predispositiongenes. However, this tool does not interpret and present resultsregarding the strength of the personal and family history as a diseaserisk factor, which might be more easily understood and acted upon byconsumers and health professionals, and it does not provide feedbackdescribing the aspects of the personal and family health histories thatare associated with the disease of interest including an explanation asto why a hereditary syndrome might be possible.

Familial risk assessment technologies that are in accordance with anembodiment of the invention can play a major role in clinical medicineand research by allowing clinicians and researchers the ability tomeasure the strength of the personal and family health histories as riskfactors for a disease of interest for patients or research participants.Clinicians and researchers can use this information to stratify theirpopulations according to the level of familial risk for a disease, whichcan inform analyses performed by the researcher or recommendations fordisease management, early detection or prevention made by the clinician.Similarly, individuals have the ability to maintain and update theirpersonal and family health history records at their convenience (e.g.,at home) and they can discuss the implications of their familial riskassessment for one or more diseases with their healthcare providersduring visits.

The technology can be used on a standalone computer system or vianetworked computers via local networks and/or the Internet increasingthe opportunities for evidence-based medicine to be integrated intomedical practice on a daily basis. The technology can be integratedwithin a researcher's database or a healthcare administration'selectronic medical records or information systems allowing for increaseddata access and interchange. Such applications and technology also lendthemselves to personalized medicine, home-based health management,including personal health records.

Example 10 Example Computer System for Conducting Analysis

FIG. 25 and the following discussion provide a brief, generaldescription of a suitable computing environment for software (forexample, computer programs) that can be written to implement thedifferent embodiments of the invention described above. The methodsdescribed above can be implemented in computer-executable instructions(for example, organized in program modules). The program modules caninclude the routines, programs, objects, components, and data structuresthat perform the tasks and implement the data types for implementing thetechniques described above.

While FIG. 25 shows a typical configuration of a desktop computer, thetechnologies may be implemented in other computer system configurations,including multiprocessor systems, microprocessor-based or programmableconsumer electronics, minicomputers, mainframe computers, and the like.The technologies may also be used in distributed computing environmentswhere tasks are performed in parallel by processing devices to enhanceperformance. For example, tasks can be performed simultaneously onmultiple computers, multiple processors in a single computer, or both.In a distributed computing environment, program modules may be locatedin both local and remote memory storage devices. For example, code canbe stored on a local machine/server for access through the Internet,whereby data from assays can be uploaded and processed by the localmachine/server and the results provided for printing and/or downloading.

The computer system shown in FIG. 25 is suitable for implementing thetechnologies described herein and includes a computer 5820, with aprocessing unit 5821, a system memory 5822, and a system bus 5823 thatinterconnects various system components, including the system memory tothe processing unit 5821. The personal computer 5820 can further includea hard disk drive 5827, a magnetic disk drive 5828, for example, to readfrom or write to a removable disk 5829, and an optical disk drive 5830,for example, for reading a CD-ROM disk 5831 or to read from or write toother optical media. The drives and their associated computer-readablemedia provide nonvolatile storage of data, data structures,computer-executable instructions (including program code such as dynamiclink libraries and executable files), and the like for the personalcomputer 5820. Although the description of computer-readable media aboverefers to a hard disk, a removable magnetic disk, and a CD, it can alsoinclude other types of media that are readable by a computer, such asmagnetic cassettes, flash memory cards, DVDs, and the like.

A user may enter commands and information into the personal computer5820 through a keyboard 5840 and pointing device, such as a mouse 5842.Other input devices (not shown) may include a microphone, joystick, gamepad, satellite dish, scanner, or the like. A monitor 5847 or other typeof display device is also connected to the system bus 5823 via aninterface, such as a display controller or video adapter 5848. Inaddition to the monitor, personal computers typically include otherperipheral output devices (not shown), such as speakers and printers.

The above computer system is provided merely as an example. Thetechnologies can be implemented in a wide variety of otherconfigurations. Further, a wide variety of approaches for collecting andanalyzing family history data and personal health data are possible. Forexample, the data can be collected and analyzed, and the resultspresented on different computer systems as appropriate. In addition,various software aspects can be implemented in hardware, and vice versa.Further, paper-based approaches to the technologies are possible,including, for example, purely paper-based approaches that utilizeinstructions for interpretation of algorithms, as well as partiallypaper-based approaches that utilize scanning technologies and dataanalysis software.

Example 11 Example Computer-Implemented Methods

Any of the computer-implemented methods described herein can beperformed by software executed in an automated system (for example, acomputer system). Fully-automatic (for example, without humanintervention) or semi-automatic operation (for example, computerprocessing assisted by human intervention) can be supported. Userintervention may be desired in some cases, such as to adjust parametersor consider results. Such software can be stored on one or morecomputer-readable media comprising computer-executable instructions forperforming the described actions.

OTHER EMBODIMENTS AND ALTERNATIVES

The techniques described above classify and explain an individual'slevel of familial risk for one or more diseases of interest. Anembodiment of the invention is a set of familial risk matrices (for aparticular disease of interest) that are designed to ensure thateveryone who is “looked up” in these matrices is classifiable regardingtheir familial risk; it is not limited to identification of onlyhigh-risk individuals or people that meet criteria for a specifichereditary syndrome.

One embodiment is a method for determining the extent to which personaland family health histories play a role in developing a disease ofinterest in a subject, the method comprising: obtaining the subject'spersonal and family health histories including one of the groupconsisting of history of the disease of interest, history of indicatordiseases, and history of indicator traits; and referencing a familialdisease risk matrix using the subject's obtained personal and familyhealth histories to find the subject's assigned level of familial riskof the disease of interest.

Another embodiment is a comprehensive method of pedigree (personal andfamily history) analysis that assigns a level of familial risk for adisease of interest through recognition of patterns of disease in thepersonal and family medical histories of a subject that are associatedwith increased disease risk and/or inherited forms of a disease ofinterest. The method comprises: obtaining the history of a disease ofinterest or related condition(s), for a subject and his/her first- andsecond-degree relatives including the age (or age range) at which thedisease or related condition(s) occurred, the sex of the subject oraffected family member(s), and the lineage of the affected familymember(s) (i.e., maternal, paternal, or nuclear); and referencing ahierarchical array of specific medical history characteristics, thatpertain to a disease of interest, of (1) a subject and (2) all ofhis/her first-degree and (3) second-degree relatives, that considers allpossible combinations of these medical history characteristics, whereupon the intersections of the medical history characteristics of asubject and his/her first and second-degree relatives are eachassociated with a level of risk describing the family history (e.g.,weak, moderate or strong), and through identification of allintersections that arise for any given subject for any given disease ofinterest, a determination can be made regarding the highest level offamilial risk for a disease of interest. In such an embodiment, eachintersection within the hierarchical array of the specific medicalhistory characteristics, of a subject and his/her first- andsecond-degree relatives, may further give an explanation for the givenlevel of familial risk, by citing the relevant family historycharacteristics, including the possibility that these characteristicsmay be suggestive of an inherited form of a disease.

In yet another embodiment of the invention, a comprehensive method ofpedigree (personal and family history) analysis assigns a level offamilial risk for a disease of interest through recognition of patternsof disease in the personal and family medical histories of a subjectthat are associated with increased disease risk and/or inherited formsof a disease of interest. The method comprises: obtaining the history ofa disease of interest or related condition(s), for a subject and his/herfirst- and second-degree relatives including the age (or age range) atwhich the disease or related condition(s) occurred, the sex of thesubject or affected family member(s), the type of affected familymembers, and the lineage of the affected family member(s) (i.e.,maternal, paternal, or nuclear); and consulting tables that havedisplayed all possible combinations of specific medical historycharacteristics that pertain to a disease of interest, of (1) a subject,and (2) his/her first-degree relatives and (3) second-degree relatives,as hierarchical matrices where upon the intersections of specificmedical history characteristics of a subject and his/her first- andsecond-degree relatives are each associated with a level of riskdescribing the strength of the personal and family histories (e.g.,weak, moderate or strong) as a risk factor for the disease of interest.Through identification of all intersections that arise for any givensubject for any given disease of interest, a determination can be maderegarding the highest level of familial risk for a disease of interest.In such an embodiment, each intersection of medical historycharacteristics may further give an explanation for the given level offamilial risk by citing the relevant personal and family historycharacteristics, including the possibility that these characteristicsare suggestive of an inherited form of a disease.

In yet another embodiment, a machine-readable medium containsinstructions stored therein which, when executed by a machine, implementan algorithm that determines the highest level of familial risk for adisease of interest for a subject. The algorithm automaticallyrecognizes the intersections of specific medical history characteristicsthat pertain to a disease of interest of a subject and his/her first-and second-degree relatives that are associated with the highest levelof familial risk, in response to items taken from the subject's personaland family history. Each intersection may further give an explanationfor the given level of familial risk by citing the relevant personal andfamily history characteristics, including the possibility that thesecharacteristics are suggestive of an inherited form of a disease, andwhen two or more intersections of medical history characteristics of thesame level of familial risk are identified, all of the relevantexplanations identified for each intersection of medical characteristicsmay be provided without redundancy or inconsistency according to analgorithm that considers all possible explanations of familial risk of adisease of interest.

It should be also be noted that the familial risk matrices, algorithms,or tables described above may be combined with other risk assessmenttechniques that consider other risk factors for disease, to give a morecomplete individualized risk assessment. Examples of such risk factorcategories used by other risk assessment techniques include demographicfactors (e.g., age, sex, ethnicity/race), physiologic and anthropometricmeasures (e.g., weight, height, waist circumference, blood pressure),laboratory test results (e.g., blood cholesterol, blood sugar),behaviors (e.g., smoking, exercise, diet), environmental exposures(e.g., second-hand smoke, ultraviolet radiation), and genetic markers(e.g., DNA-based genetic test results). As such, a personal and familyhistory risk table or matrix may become part of a disease riskassessment tool that in effect has multiple dimensions. Such a tool usesdemographic factors, behavior, environmental exposures and/or otherscenarios in addition to personal and family health histories, to indexinto a multi-dimensional look-up table. The “intersection” in that casewould be of at least four or more scenarios.

Having illustrated and described the principles of the invention inexample embodiments, it should be apparent to those skilled in the artthat the described examples are illustrative embodiments and can bemodified in arrangement and detail without departing from suchprinciples. Techniques from any of the examples can be incorporated intoone or more of any of the other examples.

In view of the many possible embodiments to which the principles of theinvention may be applied, it should be understood that the illustrativeembodiments are intended to teach these principles and are not intendedto be a limitation on the scope of the invention. For example, thefunctionality of a matrix, array, or look-up table may be implemented ina computer program using only if-then statements or using an expertsystem. I therefore claim as my invention all that comes within thescope and spirit of the following claims and their equivalents.

1. A method for determining familial risk of a disease of interest for asubject, the method comprising: obtaining, from the subject, informationcomprising: (i) whether any first- or second-degree relatives havedeveloped the disease of interest; (ii) whether any first- orsecond-degree relatives have developed an indicator disease, other thanthe disease of interest, associated with an increased risk of developingthe disease of interest; obtaining for any first- or second-degreerelative that developed the disease of interest or indicator diseaseinformation comprising: (i) an age of onset at which the disease ofinterest or indicator disease developed; (ii) a number of first-degreerelatives of the subject that developed the disease of interest orindicator disease; (iii) a number of second-degree relatives of thesubject that developed the disease of interest or indicator disease; andassigning the familial risk of the disease of interest for the subjectbased on: (i) whether any relative that developed the disease ofinterest or indicator disease was a first- or second-degree relative;(ii) the age of onset of the disease of interest or indicator disease inthe relative; (iii) the number of first-degree relatives that developedthe disease of interest or indicator disease; and (iv) the number ofsecond-degree relatives that developed the disease of interest orindicator disease.
 2. The method of claim 1 wherein the disease ofinterest is a lineage-associated disease in which lineage of the first-or second-degree relative is associated with different degrees offamilial risk of the disease of interest, and the assigning familialrisk comprises assigning the familial risk based on lineage of thefirst- or second-degree relative.
 3. The method of claim 1 wherein thedisease of interest is a gender-associated disease in which gender ofthe first- or second-degree relative is associated with differentdegrees of familial risk of the disease of interest, and the assigningfamilial risk comprises assigning the familial risk based on gender ofthe first- or second-degree relative.
 4. The method of claim 1 whereinthe method is an interactive computer implemented method for determiningthe familial risk of disease for a subject.
 5. A computer-implementedmethod for determining familial risk of disease, comprising: receivingpersonal and family member health history information; determining thefamilial risk of a disease of interest for the subject based on: (i)whether the subject has or has had the disease of interest, an indicatordisease, or an indicator trait associated with the disease of interest;(ii) whether any family member who has or has had the disease ofinterest or an indicator disease or an indicator trait was a first- orsecond-degree relative. (iii) an age of onset of the disease of interestor indicator disease or indicator trait for the subject and hisrelatives; (iv) a number of first-degree relatives that have or have hadthe disease of interest, indicator disease, or indicator trait; (v) anumber of second-degree relatives that have or have had the disease ofinterest or indicator disease or indicator trait; and providing resultsindicating the familial risk of the disease of interest for the subject.6. A method for determining the extent to which personal and familyhealth histories play a role in developing a disease of interest in asubject, the method comprising: obtaining the subject's personal andfamily health histories including a history of one of the groupconsisting of a) the disease of interest, b) indicator diseases, and c)indicator traits; and looking up the subject's assigned level offamilial risk of the disease of interest in an array of elements byindexing into the array using a plurality of items taken from thepersonal and family health histories, wherein each element of the arraygives a predetermined level of familial risk for the disease ofinterest.
 7. The method of claim 6 wherein each element of the arrayfurther gives a familial risk clarifier that clarifies or furtherexplains the assignment of familial risk of the disease of interest inthat element.
 8. A machine-readable medium having instructions storedtherein which, when executed by a machine, implement an algorithm fordetermining an assigned level of familial risk of a disease of interestfor a subject, wherein the algorithm is to automatically provide theassigned level as including one of a low level, a medium level and ahigh level, based on the subject's personal and family health histories.9. The machine-readable medium of claim 8 wherein the algorithmimplements a multi-dimensional look-up table comprising: a plurality ofpersonal disease history scenarios on a first axis of the table; aplurality of first familial disease history scenarios on a second axisof the table; a plurality of second familial disease history scenarioson a third axis of the table; and a plurality of table elements each ofwhich represents an intersection of the personal and first and secondfamilial disease history scenarios and provides an assigned level offamilial risk for the disease of interest.
 10. The machine-readablemedium of claim 9 further comprising instructions, which automaticallyprovide an explanation for the assigned level of familial risk, byciting relevant personal and family history characteristics of thesubject, based on a reference in the respective intersection.
 11. Themachine-readable medium of claim 10 wherein the explanation indicatesthe characteristics are suggestive of an inherited form of the diseaseof interest.
 12. The machine-readable medium of claim 9 furthercomprising instructions, which automatically provide an explanation forthe assigned level of familial risk, by citing relevant personal andfamily history characteristics of the subject.